Reviewβ-Lactam plus aminoglycoside or fluoroquinolone combination versus β-lactam monotherapy for Pseudomonas aeruginosa infections: A meta-analysis
Introduction
Pseudomonas aeruginosa is among the leading causes of infections in hospitalised and immunocompromised patients and is associated with significant morbidity and mortality [1], [2]. It has been suggested that a combination of antibiotics might be more effective than monotherapy at least for severe infections, and combination therapy with a β-lactam plus an aminoglycoside or a fluoroquinolone has been proposed in the guidelines of several medical associations [3]. Findings of in vitro studies suggested that synergism was accomplished against P. aeruginosa strains when two drugs that target a different or even the same bacterial mechanism are combined [4], [5]. Similar studies suggested that development of resistance is prevented by combination antibiotic regimens [6], [7]. Furthermore, in an era of increasing antibiotic resistance, adequate empirical treatment is more likely with the use of a combination of antibiotics.
Several efforts have been made through meta-analyses of randomised controlled trials (RCTs) to investigate whether combination antibiotic therapy was associated with better clinical outcomes than monotherapy. However, these meta-analyses either included a small number of patients with P. aeruginosa infections, or a variety of antibiotic classes were compared in the treatment arms of the included studies [8], [9], [10], [11]. We aimed to review systematically and to synthesise the published evidence with the methodology of meta-analysis in order to examine whether combination antibiotic therapy of β-lactam with either aminoglycoside or fluoroquinolone was associated with more favourable clinical outcomes compared with β-lactam monotherapy in patients with P. aeruginosa infections.
Section snippets
Literature search
A systematic search was performed in the PubMed and Scopus databases until April 2012. The following search term was applied: ‘(pseudomonas OR aeruginosa) AND (combination OR monotherapy) AND (mortality OR outcome)’. The bibliographies of relevant studies were also hand-searched to identify additional potentially eligible studies. Articles published in languages other than English, German, French, Spanish, Italian or Greek were not evaluated. Unpublished studies presented at scientific
Results
Fig. 1 shows the process used for article selection. Nineteen articles from those retrieved from the literature search were included [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]. A total of 8675 patients were enrolled, of whom 1721 had P. aeruginosa infections. Table 1 shows the reason for exclusion of RCTs from the meta-analysis.
Table 2 shows the characteristics of the 19 selected studies and their outcomes. Eight studies
Discussion
The published available evidence suggests that the combination of a β-lactam with an aminoglycoside or fluoroquinolone does not result in a survival benefit in patients with P. aeruginosa infections compared with β-lactam monotherapy. Most of the studies reported on mortality of patients receiving definitive treatment. Fewer data regarding empirical treatment were available. In addition, all but one of the studies that provided data on mortality were non-randomised, and none of those that
References (46)
- et al.
Reappraisal of attributable mortality in critically ill patients with nosocomial bacteraemia involving Pseudomonas aeruginosa
J Hosp Infect
(2003) - et al.
Hospital mortality for patients with bacteremia due to Staphylococcus aureus or Pseudomonas aeruginosa
Chest
(2004) Aminoglycosides plus β-lactams against Gram-negative organisms. Evaluation of in vitro synergy and chemical interactions
Am J Med
(1986)- et al.
Clinical implications of β-lactam–aminoglycoside synergism: systematic review of randomised trials
Int J Antimicrob Agents
(2011) - et al.
Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis
Lancet Infect Dis
(2004) - et al.
Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?
Lancet
(1998) - et al.
Aztreonam therapy in neutropenic patients with cancer
Am J Med
(1986) - et al.
Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance
Clin Microbiol Infect
(2012) - et al.
Outcomes of extended infusion piperacillin/tazobactam for documented Gram-negative infections
Diagn Microbiol Infect Dis
(2009) - et al.
Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis
Lancet Infect Dis
(2002)
Infectious Diseases Society of America, Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia
Am J Respir Crit Care Med
In vitro synergistic activities of aminoglycosides and new β-lactams against multiresistant Pseudomonas aeruginosa
Antimicrob Agents Chemother
Efficacy of single-agent therapy with azlocillin, ticarcillin, and amikacin and β-lactam/amikacin combinations for treatment of Pseudomonas aeruginosa bacteremia in granulocytopenic rats
Am J Med
Emergence of resistance after therapy with antibiotics used alone or combined in a murine model
J Antimicrob Chemother
β Lactam monotherapy versus β lactam–aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials
BMJ
β Lactam monotherapy versus β lactam–aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis
BMJ
Impact of definitive therapy with β-lactam monotherapy or combination with an aminoglycoside or a quinolone for Pseudomonas aeruginosa bacteremia
PLoS One
Pseudomonas bacteremia. Retrospective analysis of 410 episodes
Arch Intern Med
Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: retrospective analysis of 245 episodes
Arch Intern Med
Efficacy and safety evaluation of fixed dose combination of cefepime and amikacin in comparison with cefepime alone in treatment of nosocomial pneumonia patients
Curr Clin Pharmacol
Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients
Antimicrob Agents Chemother
A multicenter, double-blind, placebo-controlled trial comparing piperacillin–tazobactam with and without amikacin as empiric therapy for febrile neutropenia
Clin Infect Dis
Pseudomonas aeruginosa bloodstream infections: risk factors and treatment outcome related to expression of the PER-1 extended-spectrum β-lactamase
BMC Infect Dis
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